Pivotal phase 2 MonumenTAL-1 results of talquetamab (tal), a GPRC5DxCD3 bispecific antibody (BsAb), for relapsed/refractory multiple myeloma (RRMM).
Authors: Carolina D. Schinke, Cyrille Touzeau, Monique C. Minnema, Niels W.C.J. van de Donk, Paula Rodríguez-Otero, Maria-Victoria Mateos, Leo Rasche, Jing Christine Ye, Deeksha Vishwamitra, Xuewen Ma, Xiang Qin, Michela Campagna, Tara J. Masterson, Brandi Hilder, Jaszianne A. Tolbert, Thomas Renaud, Jenna Goldberg, Christoph Heuck, Ajai Chari
Journal: Journal of Clinical Oncology (2023)

8036 Background: Tal is a first-in-class BsAb targeting the novel antigen G protein–coupled receptor family C group 5 member D. In MonumenTAL-1 (NCT03399799/NCT04634552), tal showed promising efficacy and clinically manageable safety in patients (pts) with RRMM. We report pivotal phase 2 results in pts with and without prior T-cell redirection therapy. Methods: Eligible pts were intolerant to or progressed on established therapies (phase 1) or had ≥3 prior lines of therapy (LOT), including ≥1 proteasome inhibitor, ≥1 immunomodulatory drug, and ≥1 anti-CD38 antibody (phase 2). Pts received RP2Ds of SC tal 0.4 mg/kg QW or 0.8 mg/kg Q2W with step-up doses. CRS and ICANS were graded by ASTCT criteria; all other AEs were graded by CTCAE v4.03. Response was assessed by IMWG criteria. Data cut-off was Sep 12, 2022 for efficacy and Oct 19, 2022 for safety. Data will be updated for the meeting. Results: From the pivotal cohorts, 288 pts received tal 0.4 mg/kg QW (n = 143) or 0.8 mg/kg Q2W (n = 145), and 51 pts with prior T-cell redirection therapy received either dose. In the QW, Q2W, and prior T-cell redirection cohorts, respectively, median prior LOT was 5–6; 74%, 69%, and 84% were triple-class refractory and 29%, 23%, and 41% were penta-drug refractory; 15%, 11%, and 12% received prior belantamab. In the prior T-cell redirection cohort, 71% received CAR-T therapy, 35% received a BsAb, and 6% received both. In the pivotal cohorts, ORR was 74% (QW, 14.9 mo median follow-up [mF/U]) and 73% (Q2W, 8.6 mo mF/U), with very good partial response or better (≥VGPR) in 59% (QW) and 57% (Q2W). ORR was consistent across subgroups, including baseline ISS stage III disease, cytogenetic risk, number of prior LOT, and belantamab exposure. In pts with baseline plasmacytomas, ORR was 49% in both pivotal cohorts. In the prior T-cell redirection cohort, ORR was 63% (53% ≥VGPR) at 11.8 mo mF/U. Median PFS was 7.5, 11.9 (61% censored), and 5.1 mo in the QW, Q2W, and prior T-cell redirection cohorts, respectively. Common AEs included CRS (79%, 75%, 77%), skin-related AEs (56%, 71%, 69%), nail-related AEs (54%, 53%, 61%), and dysgeusia (50%, 48%, 61%); most were grade 1/2 and clinically manageable. ICANS occurred in 11%, 11%, and 3% of pts. Infections occurred in 58%, 65%, and 71% (grade 3/4: 22%, 16%, 26%) of pts, with low rates of opportunistic infections. AEs resulted in dose reductions in 15%, 8%, and 10% of pts and discontinuation in 5%, 8%, and 6%. There were no tal-related deaths. Responders to tal had higher T cell counts and lower frequencies of exhausted T cells and CD38+ Tregs vs non-responders. Conclusions: Pivotal phase 2 tal data showed &gt; 70% ORR in heavily pretreated pts with RRMM. High response rates were also seen in pts with prior T-cell redirection therapy. The safety profile was clinically manageable with low rates of high-grade infections and tal discontinuations. Clinical trial information: NCT03399799 , NCT04634552 .